Epilepsies are a group of disorders characterized by chronic and paroxysmal alterations in neurologic function associated with deviate changes in the electrical activity of the brain. They are estimated to occur between 0.5% and 2.0 percent of the population, and may occur at any age (“Harrison's Principles of Internal Medicine,” 13th Edition, 1994, Isselbacher et al., Editors, McGraw-Hill, New York). Each episode of this type neurologic dysfunction is called a seizure. They may be convulsive when accompanied by motor manifestations, or may be manifest by other abnormal changes in neurologic function such as sensory, cognitive, or emotional events. Epilepsy can be induced as a result of neurologic injury or a structural brain lesion that can occur as part of other known systemic medical disorders.
About 3.0% of the United States population has recurrent, unprovoked epilepsy (W. A. Hauser, and D. C. Hesdorfer, “Epilepsy: Frequency, Causes and Consequences,” New York: Demos., 1990, 21–28). The estimated prevalence of active epilepsy is 6.4 cases per 1000 population. This means that over 1.5 million people have active epilepsy manifest as seizures (A. V. Delgado-Escueta et al., Adv. Neurol., 44: 1–120, 1986).
The annual incidence of epilepsy ranges from 20 to 70 cases per 100,000 (S. D. Shorvon, Lancet, 1990, 336: 93–96). About 30% of patients with seizures have an identifiable neurologic or systemic disorder (D. W. Chadwick, Lancet, 1990, 336: 291–295), and the remainder have idiopathic or cryptogenic epilepsy. The diagnosis is based on the description of the seizures and the clinical context in which they occur. This is often further supplemented by results obtained EEG evaluations. Epileptic seizures have varied manifestations, and it becomes important to endeavor to classify the kind of seizure in order to select an appropriate and effective treatment. Since it is important to classify the type of seizure to choose the most suitable medical treatment, a useful classification of seizures, based on that structured by the International League against Epilepsy in 1981 is outlined in Table 1:
TABLE 1CLASSIFICATION OF EPILEPTIC SEIZURES**Primary Generalized Seizures (convulsive or non-convulsive)Tonic-Clonic (grand mal)TonicAbsence (petit mal)Atypical absenceMyoclonicAtonicInfantile spasmsPartial or Focal Seizures (beginning locally)Simple partial seizures (without impaired consciousness)With motor symptomsWith somatosensory or special sensory symptomsWith autonomic symptomsWith psychological symptomsComplex partial seizures (with impaired consciousness)Simple partial onset followed by impaired consciousnessImpaired consciousness at onset**“Harrison's Principles of Internal Medicine,” 13th Edition, 1994, Isselbacher et al., Editors, McGraw-Hill, New York; M. J. Brodie and M. A. Dichter, N. E. Jour. Med., 334:168–175, 1996.
The pathologic origins of many seizure foci in the human brain include congenital defects, head trauma and hypoxia at birth, inflammatory vascular changes subsequent to infectious pediatric illnesses, concussions or depressed skull fracture, abscess, neoplasm, vascular occlusion.
Epilepsy is a complex disease process with various, little-understood etiologies. Despite the variety of drugs used in humans to treat epileptic seizures, 20 to 40% of epileptic patients fail to experience satisfactory seizure control with currently available drugs. A clinically useful anticonvulsant drug can affect either the initiation of an epileptic discharge, or its spread within the brain. In either case, the drug ultimately must attenuate or alter neuronal excitability. This may be attained by at least three different mechanisms: modulation of voltage-dependent ions channels, enhancement of inhibitory pathways in the CNS, or suppression of excitatory pathways (Rogawski et al., 1990, Pharmacol. Rev., 42: 223–286).
Two general ways are currently thought to characterize the ways by which drugs might attenuate or abolish seizures: (1) effects on pathologically altered neurons at seizure foci to prevent or reduce their initiating excessive discharge, and (2) effects that may impede or block the spread of the excitation from the initiating foci, and thereby prevent detonation and the associated disruption of normal function by aggregates of neurons located quite distant from the seizure foci. As to our knowledge of the mechanisms of action at the intracellular or molecular level, it must be admitted that mechanisms for the beneficial action of anti-epileptic agents remains poorly understood, but is currently an expanding region for many neurological investigations.
The physician who treats patients with epilepsy encounters the task of selecting an appropriate drug or combination of drugs that may best control, seizures in a given patient at an acceptable level of adverse effects. Generally, complete control (90–100%) of seizures may be attained in as much as 50% of patients, and another 25% may evidence significant reductions in the incidence of seizures.
The classification of seizures given in the above table may be further simplified in terms of clinical experience. Absence seizures respond well to one group of drugs, and generalized tonic-clonic convulsions are generally well controlled by another. Complex partial seizures tend to be refractory to any therapy, but may show some response to the second group.
Infantile spasm and akinetic, atonic and myoclonic seizures are groups which respond very inadequately to the above two classes of drugs. Furthermore, more than one anticonvulsant drug may be required to treat patients diagnosed with two or more types of seizures (L. Goodman and A. Gilman, “The Pharmacoloical Basis of Therapeutics,” 7th Ed., 1985, MacMillan, New York; 8th Ed., 1990, MacMillan-Pergamon, New York).
Experimentally Induced Seizures. The electroshock technique for producing experimental convulsions in the intact animal for testing chemical substances for anticonvulsant activity (T. J. Putnam and H. H. Merritt, 1937, Science, 85: 525–526) provided a practical means for the evaluation of chemical agents for the management of epilepsy prior to their administration to man. Their demonstration of anticonvulsant action and anti-epileptic efficacy of phenytoin was provided a successful treatment for many patients with uncontrolled epilepsy. The success of their animal testing program showed that an experimental method could lead to the discovery of compounds that would be clinically effective. R. K. Richards and G. M. Everett, 1944 (Fed. Proc., 3: 39) found that trimethadione prevented threshold seizures induced in rodents with pentylenetetrazol, and that such seizures were also prevented by phenobarbital, but not by phenytoin. Subsequently, Goodman and associates (Proc. Am. Fed. Clin. Res., 2: 100–101, 1945; Jour. Phamacol. Exper. Ther., 108: 168–176, 1953) found that that phenytoin and phenobarbital, but not trimethadione, modified that pattern of experimental maximal electroshock seizures. These cited researches demonstrated in animals the significant different clinical anticonvulsant actions of these drugs. W. G. Lennox (Jour. Am. Med. Assn., 129: 1069–1074, 1945; Jour. Am. Med. Assn., 134: 138–143, 1947) found that trimethadione was effective in epileptic patients suffering from petit mal, as well as myoclonic or akinetic seizures that could not be controlled by phenytoin or phenobarbital. He also found that trimethadione decreased or stopped their petit mal attacks, but failed to control grand mal attacks in 10 patients in which this type of seizure predominated (R. L. Krall et al., Epilepsia, 19: 193–408, 1978).